Mass spectrometry (MS) describes a variety of instrumental methods of qualitative and quantitative analysis that enable ionizable components of a sample to be resolved according to their mass-to-charge ratios. For this purpose, a mass spectrometer converts the sample components into ions, sorts or separates the ions based on their mass-to-charge ratios, and processes the resulting ion output (ion current, flux, beam, etc.) as needed to produce a mass spectrum. Typically, a mass spectrum is a series of peaks indicative of the relative abundances of charged components as a function of mass-to-charge ratio. The information represented by the ion output can be encoded as electrical signals through the use of an appropriate transducer to enable data processing by both analog and digital techniques. An ion detector is a type of transducer that converts ion current to electrical current and thus is commonly employed in an MS system.
Insofar as the present disclosure is concerned, MS systems are generally known and need not be described in detail. Briefly, a typical MS system generally includes a sample inlet system, an ion source or ionization system, a mass analyzer (also termed a mass sorter or mass separator), an ion detector, a signal processor, and readout/display means. Additionally, the modern MS system includes an electronic controller such as a computer or other electronic processor-based device for controlling the functions of one or more components of the MS system, storing information produced by the MS system, providing libraries of molecular data useful for analysis, and the like. The electronic controller may include a main computer that includes a terminal, console or the like for enabling interface with an operator of the MS system, as well as one or more modules or units that have dedicated functions such as instrument control and data acquisition and processing. The MS system also includes a vacuum system to enclose the mass analyzer in a controlled, evacuated environment.
In operation, the sample inlet system introduces a small amount of sample material to the ion source. In hyphenated techniques, the sample inlet system may be the output of an analytical separation instrument such as employed for chromatography, electrophoresis, solid-phase extraction, or other techniques. The ion source converts components of the sample material into a stream of positive and negative ions. One ion polarity is then accelerated into the mass analyzer. The mass analyzer separates the ions according to their respective mass-to-charge ratios. The mass analyzer produces a flux of mass-resolved ions and the ions are collected at the ion detector. The mass analyzer may be of the time-sequenced type such as an ion trap, a Fourier Transform (FT) device, or an ion cyclotron resonance (ICR) device, or may be of the continuous-beam type such as a multipole device, a time-of-flight (TOF) device, or an electric or magnetic sector device.
In certain hyphenated techniques, such as tandem MS or MS/MS, more than one mass analyzer (and more than one type of mass analyzer) may be used. As one example, an ion source may be coupled to a multipole (for example, quadrupole) structure that acts as a first stage of mass separation to isolate molecular ions of a mixture. The first analyzer may in turn be coupled to another multipole structure (normally operated in an RF-only mode) that performs a collision-focusing function and is often termed a collision chamber or collision cell. A suitable collision gas such as argon is injected into the collision cell to cause fragmentation of the ions and thereby produce daughter ions. This second multipole structure may in turn be coupled to yet another multipole structure that acts as a second stage of mass separation to scan the daughter ions. Finally, the output of the second stage is coupled to an ion detector. Instead of multipole structures, magnetic and/or electrostatic sectors may be employed. Other examples of MS/MS systems include the Varian Inc. 1200 series of triple-quadrupole GC/MS systems commercially available from Varian, Inc., Palo Alto, Calif., and the implementations disclosed in U.S. Pat. No. 6,576,897, assigned to the assignee of the present disclosure.
As previously noted, the ion detector functions as a transducer that converts ionic information (which may be mass-discriminated by a mass analyzer) into electrical signals suitable for processing/conditioning by the signal processor, storage in memory, and presentation by the readout/display means. A typical ion detector is an electron-multiplier (EM). The electron multiplier includes, as a first stage, an ion-to-electron conversion device. Ions from the mass analyzer are focused toward the ion-to-electron conversion device. The ion-to-electron conversion device typically includes a surface that emits electrons in response to impingement by ions. The conversion rate mainly depends on the ion's mass, thermal state, charge state, and velocity, and the type of impact surface. The ion conversion stage is followed by an electron multiplier stage. A voltage potential is impressed across the length of a containment structure of the electron multiplier. The electrical current resulting from the ion-to-electron conversion is amplified in the multiplier stage through multiplication of liberated electrons. The gain of this multiplication can be influenced by the applied voltage potential. An anode positioned at the end of the multiplier collects the multiplied flux of electrons and the resulting electrical output current is transmitted to subsequent processes such as a current-to-voltage converter. Another type of ion detector is the photo-multiplier (PM). As appreciated by persons skilled in the art, a photo-multiplier may be substituted for an ion detector and operated in an analogous manner.
In MS systems, the ion current input into electron multiplier may range, for example, from about 10−1 ions (ion counts) per second to greater than 1012 ions per second. Electron multipliers provide an electrical current gain that may range, for a given construction, from 103 to 109 depending on applied control voltage. In the present context, the gain of the electron multiplier may be expressed as the ratio of its output electrical current to its input ion current. Hence, the output of an ion detector equipped with an electron multiplier is an amplified electrical current proportional to the intensity of the ion current fed to the ion detector, the ion-to-electron conversion rate, and the gain of the electron multiplier. This output current can be processed as needed to yield a mass spectrum that can be displayed or printed by the readout/display means. A trained analyst can then interpret the mass spectrum to obtain information regarding the sample material processed by the MS system.
Like many analytical techniques, figures of merit are associated with the performance of a mass spectrometer. From the above description of the function of the ion detector, it can be seen that the performance of the ion detector and associated collection electronics can significantly affect the performance of the mass spectrometer as a whole. Two important figures of merit are sensitivity and dynamic range, which in the present context can provide a measure of the performance of the ion detector employed in an MS system or other system employing an ion detector. To optimize sensitivity, the detector system needs to be able to detect a single ion entering the ion detector (i.e., single ion counting). To achieve this, the gain of the ion detector is increased until the output current signal exceeds all other sources of noise, with an S/N of about 5:1 when a single ion enters the ion detector. Dynamic range may be characterized as being the range in which the output response to the ion input signal is linear. Dynamic range may be limited by the signal processing circuitry that follows the ion detector or by the maximum allowable output current of the electron multiplier. For example, analog-to-digital converters (ADCs) are often provided to transform the analog signals generated by the ion detector to digital signals in order to take advantage of computerized data acquisition hardware and software. In this case, the dynamic range of an ion detector system can be limited to the maximum input signal range of the ADC. To compensate for this limitation, a user of an MS system has traditionally reduced the gain of the electron multiplier by lowering the high-voltage supplied to the electron multiplier. However, this will result in losing sensitivity because single ions can no longer be detected. Increasing sensitivity such as by increasing gain may exceed the maximum allowable output current of the electron multiplier, and/or prematurely stress or age the specialized material that comprises the surfaces of the electron multiplier. These surfaces are designed to be operated at a gain that results in an optimum output current providing a good S/N ratio and reasonable service life. The means taken for extending dynamic range may reduce sensitivity, lower the precision of detected mass peaks, and, if a high sensitivity is selected, narrow the bandwidth of amplifiers employed in signal processing and/or limit the maximum scan speed of the mass analyzer. Moreover, there has not existed a sufficient method for increasing both dynamic range and sensitivity, or at least increasing dynamic range without adversely affecting sensitivity.
U.S. Pat. No. 7,047,144, commonly assigned to the assignee of the present disclosure, describes apparatus and methods for increasing the dynamic range of an ion detector by changing the gain of the ion detector for each following scan if necessary. After each scan, the digital output signal of the ion detector is then back scaled according to the gain on the ion detector to provide the mass spectrum. The invention disclosed in this patent has been successfully tested and implemented, but may be considered as having some drawbacks. For instance, because the gain is set only once per scan, the dynamic range and sensitivity of all data within that scan is effectively limited to the ion detector gain set for this scan. It is therefore desirable to change the ion detector gain on every sample, rather than on every scan. To improve scan speeds, it is also desired to be able to collect data points very rapidly, for example, every 10 μs for a quadrupole-based MS or every 1 μs for an ion trap-based MS. To change the gain of the electron multiplier by 103, for example, one would need to change the control voltage to the multiplier by about 600 V. Therefore, the implementation of an extended dynamic range technique on a sample-by-sample basis would require a DC amplifier with close to a 600 V/μs slew rate, which in practice is very difficult to do and would require a large amount of power. Additionally, if it is desired to have an ion deprecation accuracy of better than 0.01%, this DC amplifier would also need to be able to settle its output voltage to within 5 V within one sample. In addition, while waiting until the ion detector gain changes, one cannot collect data because the gain of the multiplier would be unknown during this time.
Accordingly, there continues to be a need for improved techniques for optimizing sensitivity and dynamic range in mass spectrometers utilizing ion detectors. In particular, there is a need for optimizing multiplier gain at a rate faster than a scan-by-scan basis, and for optimizing multiplier gain independently of the ion sampling rate.